1. Field of the Invention
The present invention relates to a process for preparing a prodrug formulation of ganciclovir and its pharmaceutically acceptable salts. More specifically, the invention relates to a process for preparing the mono-L-valine ester derived from 2-(2-amino-1,6-dihydro-6-oxo-purin-9-yl)methoxy-1,3-propanediol and its pharmaceutically acceptable salts. The invention also relates to novel intermediates useful in the above process and to a process for preparing those intermediates.
2. Background Information
British Patent 1 523 865 describes antiviral purine derivatives with an acyclic chain in the 9-position. Among those derivatives 2-(2-amino-1,6-dihydro-6-oxo-purin-9-yl)methoxy-ethanol with the INN name acyclovir has been found to have good activity against herpes viruses such as herpes simplex.
U.S. Pat. No. 4,355,032 discloses the compound 9-[(2-hydroxy-1-hydroxy-methylethoxy)methyl]guanine or 2-(2-amino-1,6-dihydro-6-oxo-purin-9-yl)-methoxy-1,3-propanediol with the INN name ganciclovir. Ganciclovir is highly efficacious against viruses of the herpes family, for example, against herpes simplex and cytomegalovirus.
European Patent Application 0 375 329 A2 discloses prodrug compounds with the following formula ##STR3## wherein R and R.sup.1 are independently selected from hydrogen and an amino acid acyl residue, provided at least one of R and R.sup.1 represents an amino acid acyl residue and B represents a group of the formulae ##STR4## in which R.sup.2 represents a C.sub.1-6 straight chain, C.sub.3-6 branched chain or C.sub.3-6 cyclic alkoxy group, or a hydroxy or amino group or a hydrogen atom and the physiologically acceptable salts thereof. These prodrug compounds are described as having advantageous bioavailability when administered by the oral route, resulting in high levels of the parent compound in the body.
Example 3(b) of European Patent Application 0 375 329 A2 discloses the preparation of the bis-(L-isoleucinate) ester of ganciclovir as a white foam. Example 4(b) discloses the preparation of the bis(glycinate) ester of ganciclovir as a white solid. Example 5(b) discloses the preparation of the bis-(L-valinate) ester of ganciclovir as a solid. Example 6(b) discloses the preparation of the bis-(L-alaninate) ester of ganciclovir as a syrup containing 90% of the bis ester and 10% of the monoester. The bis-esters are prepared by reacting ganciclovir with an optionally protected amino acid or functional equivalent thereof. The reaction may be carried out in a conventional manner, for example in a solvent such as pyridine, dimethylformamide, etc., in the presence of a coupling agent such as 1,3-dicyclohexylcarbodiimide, optionally in the presence of a catalytic base such as 4-dimethylaminopyridine. The described bis esters are non-crystalline materials which are difficult to process for the manufacture of oral pharmaceutical dosage forms.
British Patent Application No. 8829571 is the priority patent application for European Patent Application 0 375 329 A2 and U.S. Pat. No. 5,043,339, and discloses amino acid esters of the compounds of the formula ##STR5## (wherein R represents a hydroxy or amino group or a hydrogen atom) and the physiologically acceptable salts thereof. Examples of preferred amino acids include aliphatic acids e.g. containing up to 6 carbon atoms such as glycine, alanine, valine and isoleucine. The amino acid esters include both mono and diesters. The preparation of the diesters is identical to the preparation in European Patent Application 0 375 329 A2; however, this patent application as well as European Patent Application 0 375 329 A2 and U.S. Pat. No. 5,043,339 do not disclose the preparation of monoesters, or any data suggesting their usefulness.
Leon Colla et al., J. Med. Chem. (1983) 26, 602-604, disclose several water-soluble ester derivatives of acyclovir and their salts as prodrugs of acyclovir. The authors indicate that acyclovir cannot be given as eye drops or intramuscular injections because of its limited solubility in water and have therefore synthesized derivatives of acyclovir which are more water soluble than the parent compound. The authors disclose the hydrochloride salt of the glycyl ester, the hydrochloride salt of the alanyl ester, the hydrochloride salt of the beta-alanyl ester, the sodium salt of the succinyl ester, and the azidoacetate ester. The alanyl esters were prepared by conventional esterification methods, including reacting acyclovir with the corresponding N-carboxy-protected amino acid in pyridine, in the presence of 1,3-dicyclohexylcarbodiimide and a catalytic amount of p-toluenesulfonic acid and subsequent catalytic hydrogenation to give the alpha- and beta-alanyl esters as their hydrochloride salts.
L. M. Beauchamp et al., Antiviral Chemistry & Chemotherapy (1992), 3 (3), 157-164, disclose eighteen amino acid esters of the antiherpetic drug acyclovir and their effectiveness as prodrugs of acyclovir, evaluated in rats by measuring the urinary recovery of acyclovir. Ten prodrugs produced greater amounts of the parent drug in the urine than acyclovir itself: the glycyl, D,L-alanyl, L-alanyl, L-2-amino-butyrate, D,L-valyl, L-valyl, DL-isoleucyl, L-isoleucyl, L-methionyl, and L-prolyl ester. According to the authors, the L-valyl ester of acyclovir was the best prodrug of the esters investigated. These esters were prepared by methods similar to those employed by Colla et al.
European Patent Application 0 308 065 A2 discloses. the valine and isoleucine esters of acyclovir, preferably in the L-form, as showing a large increase in absorption from the gut after oral administration, when compared with other esters and acyclovir. The amino acid esters are prepared by conventional esterification methods, including reacting acyclovir with an N-carboxy-protected amino acid or an acid halide or acid anhydride of the amino acid, in a solvent such as pyridine or dimethylformamide, optionally in the presence of a catalytic base.
PCT Patent Application WO 94/29311 discloses a process for the preparation of amino acid esters of a nucleoside analogue, including acyclovir and ganciclovir. This process comprises reacting a nucleoside analogue having an esterifiable hydroxy group in its linear or cyclic ether moiety, with a 2-oxa-4-aza-cycloalkane-1,3-dione of the formula ##STR6## wherein R.sup.1 may represent hydrogen, a C.sub.1-4 alkyl or alkenyl group or other amino acid side chains, and R.sup.2 may represent hydrogen or a group COOR.sup.3 where R.sup.3 is a benzyl, t-butyl, fluorenylmethyl or an optionally halo substituted linear or branched C.sub.1-8 alkyl group. Preferred R.sup.1 groups include hydrogen, methyl, isopropyl and isobutyl, yielding respectively the glycine, alanine, valine and isoleucine esters of acyclovir or ganciclovir.
Examples 1-3 of PCT Patent Application WO 94/29311 disclose only the condensation of acyclovir with the valine-substituted 2-oxa-4-aza-cycloalkane-1,3-dione (Z-valine-N-carboxyanhydride) by conventional procedures. While the amino acid esters of the PCT application include both the acyclovir and ganciclovir [9-((1,3-dihydroxy-2-propoxy)methyl)-guanine or DHPG]esters, the application does not disclose how to prepare the ganciclovir esters, much less the mono-esters of ganciclovir. The mono-L-valine ester derived from 2-(2-amino-1,6-dihydro-6-oxo-purin-9-yl)-methoxy-1,3-propanediol and its pharmaceutically acceptable salts are potent antiviral agents and are described in European Patent Application 0 694 547 A. These compounds have been found to have improved oral absorption and low toxicity. This patent application also discloses certain processes for preparing these esters, different from those described herein.
The present invention relates to an improved process whereby a cyclic orthoester, a monocarboxylate and a monocarboxylate-monovalinate of ganciclovir are prepared as intermediates. The monocarboxylate intermediate is formed with high selectivity and in high yields, and provides for mono-esterification by an L-valine derivative. The monocarboxylate-monovalinate can then be selectively hydrolyzed to the monovaline ester which is obtained in good yield and purity.